Diclofenac formulations and methods of use

ABSTRACT

Methods and formulations are provided for treating migraine and other acute pain episodes using diclofenac, and formulations of diclofenac that provide both rapid and sustained relief from acute pain. Methods and formulations are also provided for treating symptoms that often accompany migraine and acute pain such as photophobia, phonophobia, nausea and vomiting.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. application Ser. No.13/742,871 filed Jan. 16, 2013, now pending, which is a continuation ofU.S. application Ser. No. 12/399,175 filed Mar. 6, 2009, now abandoned,which is a Continuation of U.S. application Ser. No. 11/455,120 filedJun. 16, 2006, now U.S. Pat. No. 7,759,394 issued on Jul. 20, 2010 whichclaims the benefit of U.S. Provisional Application No. 60/691,757 filedJun. 17, 2005 and U.S. Provisional Application No. 60/692,024 filed onJun. 17, 2005, which are herein incorporated by reference in theirentirety.

FIELD OF THE INVENTION

This invention concerns methods and formulations for treating migraineand other acute pain episodes using diclofenac, and formulations ofdiclofenac that provide both rapid and sustained relief from acute pain.The invention further concerns methods and formulations for treatingsymptoms that often accompany migraine and acute pain such as reboundheadache, photophobia, phonophobia, nausea and vomiting.

BACKGROUND OF THE INVENTION

Diclofenac is a non-steroidal anti-inflammatory drug (“NSAID”) knownchemically as [(2,6-dichloro-anilino)-2-phenyl]-2-acetic acid. The drugwas developed in the 1960s by scientists at Ciba-Geigy and is soldaround the world by Novartis under various trade names, includingCataflam® and Voltaren® in the United States. A wet granulatedformulation of diclofenac potassium was recently developed to provide anincreased rate of absorption, and its pharmacokinetic properties testedagainst commercially available diclofenac potassium tablets. (Reiner etal., Increased absorption rate of diclofenac from fast actingformulations containing its potassium salt. Arzniem.-Forsch./Drug Res.2001; 51:885-890.) According to the authors, the granular formulationshowed a higher C_(max) than the diclofenac potassium tablets, a shortert_(max) (i.e. time to C_(max)) and a similar AUC when compared to thetablet form.

Owing to its excellent analgesic properties, diclofenac is widely usedfor treating various types of pain, including both chronic and acutepainful episodes. The drug is administered for the treatment ofmusculoskeletal and joint disorders such as rheumatoid arthritis,osteoarthritis, and ankylosing spondylitis; periarticular disorders suchas bursitis and tendonitis; soft tissue disorders such as sprains andstrains, and other painful conditions such as renal colic, acute gout,dysmenorrhoea, and following some surgical procedures. (Martindale(2000) Diclofenac. In: Reynolds, The Extra Pharmacopoeia. London: ThePharmaceutical Press; p. 31-33.) Diclofenac has also been studied forthe treatment of headache pain from migraine attacks, using variousdoses and dosage forms, including 75 mg. intramuscular injections (DelBene et al., Intramuscular treatment of migraine attacks usingdiclofenac sodium: a cross-over trial. J. Int. Med. Res. 1987; 1544-8),100 mg. suppositories (Del Bene et al., Migraine attack treatment withdiclofenac sodium. Cephalalgia 1985; 5:144-5), and 50 mg. enteric coatedtablets. (Massiou et al., Effectiveness of oral diclofenac in the acutetreatment of common migraine attacks: a double blind study versusplacebo. Cephalalgia 1991; 1:59-63.)

Migraine attacks manifest a diverse array of symptoms that must beresolved in order for a treatment to be deemed truly effective againstmigraine (instead of just treating the symptoms). In particular, thetreatment must be effective against the pain, photophobia, phonophobiaand nausea that are caused by migraine, and it must be effective withinthe first two hours of treatment, in order to be considered a truetreatment for migraine. None of the studies reported to date suggeststhat a 50 mg. diclofenac product could treat all of these symptomswithin two hours of treatment.

In 1993, investigators studied 100 mg. and 50 mg. diclofenac tablets, incomparison to placebo, and determined that both strengths were effectiveagainst migraine pain within two hours of treatment, but that only the100 mg. strength was effective against phonophobia and photophobiawithin two hours. (Dahlöf et al., Diclofenac-K (50 and 100 mg.) andplacebo in the acute treatment of migraine. Cephalalgia 1993;13:117-123). In 1999, a separate group of investigators tested 50 mg.and 100 mg. sugar coated tablets of diclofenac potassium to treatmigraine, and once again confirmed the ability of both doses to relievemigraine pain within two hours of treatment. (TheDiclofenac-K/Sumatriptan Migraine Study Group, Acute treatment ofmigraine attacks: efficacy and safety of a nonsteroidalanti-inflammatory drug, diclofenac potassium, in comparison to oralsumatriptan and placebo. Cephalalgia 1999; 19:232-40.) The investigatorsconcluded that neither dose was effective against photophobia two hoursafter treatment, that both doses were effective against photophobiaeight hours after treatment, that only the 100 mg dose was effectiveagainst phonophobia two hours after treatment, and that the 50 mg dosewas effective against photophobia eight hours after treatment.

The 1999 investigators also studied the effectiveness of 100 mg and 50mg. diclofenac-K immediate release tablets at preventing recurrence ofheadaches within 48 hours of treatment. The investigators concluded thatpatients treated with the 50 mg and the 100 mg diclofenac-K tabletsactually had a higher incidence of headache recurrence than patientstreated with placebo (i.e. that the diclofenac-K performed worse thanplacebo), although the statistical significance of these findings is notreported.

This latter finding is consistent with other recent literature whichrecommends the use of a “long acting NSAID” to reduce the frequency ofrebound headaches. For example, Plachetka recommends in U.S. Pat. No.6,586,458 that triptan therapy be augmented with a “long acting NSAID”to provide “a substantial reduction in the frequency [of] relapse ofheadaches.” Diclofenac potassium is not considered a long acting NSAIDbecause it displays an average C_(max) within only about one hour and aterminal half life of only about 1.9 hours when administered incommercially available sugar coated tablets.

Diclofenac is generally taken orally in the form of normal tablets ortablets covered with coatings resistant to gastric juices, or rectally,or by injection, or topically. Recently, however, in WO 97/44023, Reineret al. proposed to administer diclofenac in a number of lessconventional dosage forms—including as a powder sachet for oraladministration after dissolving in water—for quicker onset of analgesicrelief One of the primary obstacles in the manufacture of powder sachetsis the distribution of the drug in the powder, and the uniformity ofcontent in the finished product. These hurdles are magnified in theproduction of diclofenac sachets due to the poor aftertaste ofdiclofenac, and the need to incorporate additional ingredients tocompensate for this poor taste.

To ensure an adequately homogenous distribution of drug product in thebulk powder, Reiner et al. disclose a wet granulation process formanufacturing the powder sachets. In the first step of the process, awet granulate is prepared from diclofenac potassium, potassiumbicarbonate, saccharin, aspartame and mannitol, using 95% ethanol as thewetting agent. The granulate is then mixed with over one gram of sugar(saccharose) and various flavoring agents to improve the taste of thecomposition.

The method described by Reiner et al. produces an excellentpharmaceutical dosage form but suffers from a number of disadvantagesincluding the size of the sachet (2 g) which makes the sachet moredifficult to dissolve, and the presence of sugar in the formulation,which should be avoided in the diabetic population. In addition, theprocess requires precise controls on the granulometric process to assureuniform distribution of drug in the granulate and consistent amounts ofdrug in the finished product. What is needed is an alternative methodfor producing sugar-free powder diclofenac sachets and other fast actingdosage forms of diclofenac.

SUMMARY OF INVENTION

The inventors have unexpectedly discovered that rapidly bioavailableformulations of diclofenac are effective in the treatment of migraineand other acute pain episodes, and that in spite of their quick onset ofaction, they provide sustained relief against acute pain for up totwenty-four hours. Contrary to the prior art, which suggests that a longacting NSAID should be used to prevent rebound headache, and that arapidly bioavailable formulation of diclofenac would be ineffectiveagainst rebound headache, the inventors have discovered that a rapidlybioavailable formulation of diclofenac, as measured by t_(max) andC_(max), prevents recurrence of headaches for at least twenty four hoursafter treatment in a significant population of migraine sufferers. Inaddition, the consistency of bioavailability seems to improve as thebioavailability of the molecules becomes more rapid, which furthercontributes to the clinical efficacy observed for these formulations.

The inventors have also surprisingly discovered that these rapidlybioavailable formulations relieve symptoms often associated withmigraine and other acute pain, including photophobia and phonophobia,better than conventional immediate release tablets. These results aresurprisingly seen even though the diclofenac in these formulations ismore rapidly eliminated from the bloodstream than conventional immediaterelease tablets of diclofenac, and even though the total amount ofdiclofenac absorbed in the blood stream (measured as the area under thecurve (i.e. AUC_(0-∞))) is comparable for the two formulations. Theformulations are thus able to meet all of the primary clinical endpointsfor evaluating migraine treatments, and for completely treatingmigraine.

Therefore, in one embodiment the invention preferably provides a methodof treating migraine comprising: (a) providing a liquid formulationcomprising 50 mg. of diclofenac or a pharmaceutically acceptable saltthereof, wherein said formulation: (i) is provided as a unit dose powderformulation and dissolved or suspended in water immediately beforeadministration, or as a unit dose liquid formulation that is ingestedwith or without further mixing; (ii) achieves t_(max) in from about 10to about 20 minutes; and (iii) optionally but preferably achieves aC_(max) of from about 1500 to about 2500 ng/ml; and (b) orallyadministering said formulation to a patient suffering from migraine,wherein migraine is defined as a disease manifested in a population ofpatients by periodic attacks of headache pain, nausea, photophobia andphonophobia. In one particular embodiment the method is used to treatmigraine that is accompanied by photophobia and/or phonophobia. Inanother particular embodiment, the method is used to treat migrainepatients who suffer from recurrent headache, and are diagnosed asrequiring relief from recurrent headache within twenty-four hours of theinitial treatment.

In other embodiments the method is used to treat any episode of acutepain in which the pain would otherwise persist for at least about eighthours, and pain relief is required for this time period. Thus, in stillanother embodiment the invention preferably provides a method oftreating acute pain in a human patient requiring pain relief for atleast eight hours, comprising: (a) providing an oral formulationcomprising about 50 mg. of diclofenac or a pharmaceutically acceptablesalt thereof, wherein said formulation (ii) achieves t_(max) in fromabout 10 to about 35, 30, or 25 minutes; and (iii) optionally butpreferably achieves a C_(max) of from about 1400 or 1500 to about 2500ng/ml; and (b) orally administering said formulation to a patientsuffering from acute pain, preferably no more than 3 total times in a 24hour period.

In still another embodiment the invention provides an alternative methodfor preparing powder diclofenac sachets that is based predominantly onthe large proportion of mannitol in the formulation, which preferablyincludes a precise control of particle size of diluents in the finishedproduct. The large proportion of mannitol imparts surprisingly rapidbioavailability to the formulation, while the control of particle sizeassures uniform distribution of diclofenac in the material used to fillthe sachets and consistent amounts of drug in each sachet without theuse of sugar or large amounts of diluent as taught in the prior art. Themethod and powders produced by the method are characterized by, amongother variables, (1) the ratio of the diluent to the diclofenac in thepowder, (2) a combination of particle sizes of the diluent in the finalcomposition, and (3) the sequence of mixing the diclofenac and thevarying particle sizes of diluent.

The invention further provides methods for manufacturing highlyconcentrated liquid formulations of diclofenac that can be drawn asdrops from a bottle and administered after mixing the diclofenac with asuitable carrier such as water. In one aspect of this embodiment theinvention provides a method of making a liquid solution of diclofenac,wherein the diclofenac is present in the liquid at a concentration offrom about 10 to about 100 mg./ml., comprising (a) dissolving diclofenacin ethyl alcohol to form a solution, (b) mixing said solution withglycerol to form a second solution, and (c) mixing said second solutionwith water.

Additional advantages of the invention will be set forth in part in thedescription which follows, and in part will be obvious from thedescription, or may be learned by practice of the invention. Theadvantages of the invention will be realized and attained by means ofthe elements and combinations particularly pointed out in the appendedclaims. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION OF THE DRAWING

The accompanying drawing, which is incorporated in and constitutes apart of this specification, illustrates several embodiments of theinvention and together with the description, serves to explain theprinciples of the invention.

FIG. 1 is a flow diagram illustrating a non-granulate method andsequence of mixing employed in making 900 mg. powder sachets of theinstant invention that contain 50 mg. of diclofenac potassium.

DETAILED DESCRIPTION OF THE INVENTION

The present invention may be understood more readily by reference to thefollowing detailed description of preferred embodiments of the inventionand the Examples included therein.

Methods of Treating Migraine and Acute Pain

As discussed above, the invention provides novel formulations ofdiclofenac—especially diclofenac potassium—that have proven to beremarkably effective against migraine headache and other forms of acutepain. The formulations may contain various quantities of diclofenac, invarious oral dosage forms, ranging from about 12.5 mg. to about 100 mg.of diclofenac or a pharmaceutically acceptable salt thereof. Thus, forexample, the formulation can contain about 12.5, 25, 37.5, 50, 75 or 100mg of diclofenac or a pharmaceutically acceptable salt thereof, in atablet, a capsule, a powder for oral solution, an oral solution orsuspension, on orally dissolving tablet, a mucoadhesive film, or anyother orally ingestible dosage form. In a particularly preferredembodiment, however, the formulations of the present invention arepresent in a liquid form when ingested, and they contain about 50 mg. ofdiclofenac or a pharmaceutically acceptable salt thereof. In anotherpreferred embodiment, the formulations are used to treat migraineheadache.

Therefore, in one embodiment the invention provides a method of treatingmigraine comprising: (a) providing a liquid formulation comprising 50mg. of diclofenac or a pharmaceutically acceptable salt thereof, whereinsaid formulation: (i) is provided as a unit dose powder formulation anddissolved or suspended in water immediately before administration, or asa unit dose liquid formulation that is ingested with or without furthermixing; (ii) achieves t_(max) in from about 10 to about 20 minutes;(iii) optionally but preferably achieves a C_(max) of from about 1500 toabout 2500 ng/ml; and (b) orally administering said formulation to apatient suffering from migraine, wherein migraine is defined as adisease manifested in a population of patients by periodic attacks ofheadache pain, nausea, photophobia and phonophobia.

In one particular embodiment, the methods of this invention are used totreat some of the most difficult to treat migraine patients—i.e. thosewhose headache pain is likely to recur within twenty-four hours ofinitial treatment, or those who also suffer from photophobia orphonophobia. Therefore, in another embodiment the invention provides amethod of treating migraine in a human patient suffering from migrainecomprising: (a) providing a liquid formulation comprising about 50 mg.of diclofenac or a pharmaceutically acceptable salt thereof, whereinsaid formulation: (i) is provided as a powder formulation and dissolvedor suspended in water immediately before administration, or as a liquidformulation that is ingested with or without further mixing; (ii)achieves t_(max) in from about 10 to about 20 minutes; (iii) optionallybut preferably achieves a C_(max) of from about 1500 to about 2500ng/ml; and (b) diagnosing a patient suffering from migraine as requiringsustained migraine relief for at least 24 hours (such as a patient whois susceptible to rebound or recurrent headaches); and (c) orallyadministering said formulation to said patient.

Patients who are particularly well-suited for treatment by the methodsof this invention are those patients who have previously been treatedfor migraine pain using an acute pain medication, but who continued tosuffer from symptoms such as phonophobia, photophobia, nausea andvomiting, especially those individuals who required additionalmedication for these symptoms. Thus, for example, in one embodiment thepatient has previously been diagnosed as requiring relief fromphotophobia, phonophobia, nausea or vomiting in conjunction withtreatment for migraine pain. In another embodiment the method isperformed without administering other medications for the relief ofphotophobia, phonophobia, nausea or vomiting. In still anotherembodiment the method is performed without administering othermedications for the relief of migraine pain.

Therefore, in still another embodiment the invention provides a methodof treating migraine associated with phonophobia or photophobia in ahuman patient comprising: (a) providing a liquid formulation comprising50 mg. of diclofenac or a pharmaceutically acceptable salt thereof,wherein said formulation: (i) is provided as a powder formulation anddissolved or suspended in water immediately before administration, or asa liquid formulation that is ingested with or without further mixing;(ii) achieves t_(max) in from about 10 to about 20 minutes; (iii)optionally but preferably achieves a C_(max) of from about 1500 to about2500 ng/ml; and (b) orally administering said formulation to a patientsuffering from migraine associated with photophobia or phonophobia.

As discussed above, this invention also concerns methods for treatingacute pain using diclofenac, and formulations of diclofenac that provideimmediate and sustained relief from any type of acute pain. In additionto migraine headache pain, the pain may derive from a variety ofsources, including musculoskeletal and joint disorders such asrheumatoid arthritis, osteoarthritis, and ankylosing spondylitis,periarticular disorders such as bursitis and tendonitis, soft tissuedisorders such as sprains and strains, and other painful conditions suchas renal colic, acute gout, dysmenorrhoea, and following some surgicalprocedures. In one preferred embodiment the acute pain is post-operativepain, such as post-operative dental pain.

The formulations are particularly well suited for providing relief fromsustained acute pain, defined herein as acute pain that would otherwisepersist for about 4, 6 or 8 hours without the treatment contemplated bythe current invention. In one preferred embodiment the patient treatedby the method has been previously diagnosed as requiring relief fromsustained acute pain. A patient requiring sustained relief from acutepain is a patient who has either been previously diagnosed as requiringrescue medication within about 4, 6 or 8 hours of treatment for saidacute pain, or a patient whose acute pain is expected to persist for 4,6 or 8 or more hours in the absence of treatment.

In another embodiment, therefore, the invention provides a method oftreating acute pain in a human patient requiring pain relief for atleast eight hours, comprising: (a) providing an oral formulationcomprising about 50 mg. of diclofenac or a pharmaceutically acceptablesalt thereof, wherein said formulation: (i) achieves a C_(max) of fromabout 1400, 1450 or 1500 to about 2500 ng/ml; and (ii) achieves t_(max)in from about 10 to about 35, 30 or 25 minutes; and (b) orallyadministering said formulation to a patient suffering from acute pain,preferably no more than 3 total times in a 24 hour period.

The sustained relief provided by the compositions of the presentinvention provides numerous advantages in the treatment of acute pain,and leads to decreased requirements for pain medication by manypatients. Thus, in one embodiment the method is performed withoutadministering other immediate pain relief or rescue medications withinthe first 4, 6 or 8 hours of administering the diclofenac formulation.In one embodiment, the formulation is administered no more than 3 totaltimes in a 24 hour period. In another embodiment, the formulation isadministered as needed for pain every 2, 4, 6 or 8 hours (or every 4-6,4-8, or 6-8 hours), as needed for pain, preferably not to exceed threetimes per day. In yet another embodiment, the formulation isadministered once every eight hours.

As discussed above, the formulations of the present invention arepreferably administered as a liquid for oral ingestion, and can beprovided in any form suitable for such administration. In a particularlypreferred embodiment, the formulation is provided in a single unit doseas a powder sachet, which is mixed with water before administration. Inother embodiments the formulation is already dissolved in a liquid, asin the drop formulation of the present invention and the unit dose vialsdiscussed elsewhere herein. It will be understood, however, that therelief from migraine and acute pain occasioned by the methods of thepresent invention can be achieved with any oral formulation thatachieves the pharmacokinetics described herein, and that the inventionextends to any such dosage form.

Statistically Significant Relief

In some embodiments of the present invention, the medication isadministered to a plurality of patients suffering from migraine, andstatistically significant relief is observed based on one or moreprimary or secondary clinical endpoints, in comparison to placebo or 50mg. immediate release diclofenac potassium tablets (i.e. Cataflam),including:

-   -   two hour pain relief (i.e. a decrease in pain intensity from        moderate/severe to mild/none)    -   pain free at two hours    -   sustained pain relief for 6, 8 or 24 hours    -   relief from phonophobia at two hours    -   relief from photophobia at two hours    -   relief from nausea and vomiting at two hours        As noted above, the ability to attain statistically significant        relief by the methods of the present invention is greatly        influenced by the coefficients of variation in Cmax and tmax        observed for this invention, which seem to decrease as the        diclofenac in these formulations becomes more bioavailable.

Of course, every patient treated by the methods of the present inventionwill not require relief from every clinical endpoint, or obtain relieffrom every clinical endpoint. In addition, the plurality of patientsthat any individual physician or physician's practice group treats maynot rise to the level of “statistical significance,” as that term istypically used in the pharmaceutical industry (i.e. p<0.05). In thecontext of this invention, the term “statistically significant” is notbased solely upon the plurality of patients treated by the definedmethod, but takes into account well designed comparative clinical trialsversus placebo that have previously been conducted to confirm thestatistically significant relief, in addition to the clinical resultsobtained by practice of the present invention by individual patients,practitioners, or physician practice groups.

Pharmacokinetics

In one embodiment the composition is characterized by itspharmacokinetics, such as C_(max) (i.e. average concentration of activechemical in the bloodstream after oral ingestion, preferably in thefasted state), and its t_(max) (i.e. average time to reach said C_(max),in a fasted state). In a particularly preferred embodiment, the meanC_(max) for a 50 mg. diclofenac composition ranges from about 1300,1400, 1500, 1600 or 1700 to about 2600, 2500, 2300, 2100, 2000 or 1900ng/ml. A suitable range can be derived from any of these upper and lowerbounds, but in one embodiment the formulation preferably attains aC_(max) of from about 1300, 1400 or 1500 to about 2500 ng/ml; or fromabout 1500, 1600, or 1700 to about 2100 ng/ml, for a 50 mg. diclofenacformulation. It will be understood, of course that any of these C_(max)values can be normalized based on the dose administered. Thus, forexample, a 1500 ng/ml C_(max) observed for a 50 mg. dose could benormalized to 30 ng/ml·g and applied to other dose amounts. In aparticularly preferred embodiment the formulations yield only one peakconcentration when blood concentrations are plotted against time.

The median t_(max) (i.e. time to reach C_(max)) of the formulations ispreferably from about 5 or 10 to about 40, 35, 30, 25 or 20 minutes.Once again, a suitable range can be derived from any of these upper andlower bounds, but in one particular embodiment the t_(max) of theformulation is most preferably from about 10 to about 35 minutes, fromabout 10 to about 30 minutes, from about 10 to about 25 minutes, or fromabout 10 to about 20 minutes. The inter-subject coefficient ofvariability for said C_(max) preferably is less than about 70, 65, 60,55, 50, 40 or 35%, and the inter-subject coefficient of variability forsaid t_(max) is preferably less than about 70, 60, 50, 40 or 35%.

Of course, it will be understood that bioavailability can differ fromdifferent study sites. When a single formulation gives results that varysignificantly among different clinical sites and investigators, theresults can be proportionately normalized against the bioavailability ofCataflam tablets, based upon the results reported in the exampleshereto. Thus, for example, if the C_(max) that a laboratory observes forCataflam is only 750 ng/ml, all of the C_(max) results reported from thelaboratory could be adjusted by a factor of (1037.124)/(750).

Methods of Formulation

As noted previously, the invention also concerns methods of making aparticulate flowable diclofenac composition that can be defined by anumber of characteristics, including the presence of a fine powdereddiluent, the combination of fine and coarse diluent, the total amount ofdiluent, the size distribution of diclofenac particles, or the use of anon-hygroscopic diluent. These various features and aspects of thepresent invention are set forth in greater detail below.

Diclofenac

The diclofenac used in the present invention can be defined by variousparameters. In one embodiment, the raw material will be a powder thatexhibits no more than 0.5 wt. % loss on drying. In another embodimentnot less than 90% of the diclofenac particles are less than 500micrometers in diameter, not less than 40% and not more than 70% of theparticles are less than 200 micrometers in diameter, not less than 35%and not more than 65% of the particles are less than 150 micrometers indiameter, and not less than 30% of the particles are less than 100micrometers in diameter. (Analyses performed using sieves according tothe Sieve Test 2.9.12 Eur. Ph.—Alpine Air Jet Sieve.) The averageparticle size for the diclofenac powder is preferably about 150, 160,170, 180, 190, 200, 210, 220, 230, or 240 micrometers, and can rangebetween any two of the foregoing variables (i.e. from about 150 to about230 micrometers, or from about 170 to about 220 micrometers).

The diclofenac can be present in acid or salt form although, owing toits poor solubility in water, diclofenac is normally used in salt form.The salts of diclofenac customarily used are those of sodium, potassiumor other alkali and alkaline earth metals, together with salts oforganic nature, such as the salts of basic amino acids, such as lysine,arginine and ornithine, or other pharmacologically acceptable organicbases which have the ability to render the resulting salt soluble inwater. Diclofenac potassium is preferably used in this invention due toits fast onset of action.

In a preferred embodiment, 50 mg. of diclofenac or its salt is used inthe final dosage form, although other amounts could be used including12.5, 25, 37.5, 50, 75 or 100 mg of diclofenac, or a range having asendpoints any of the foregoing amounts. The amount of diclofenacpreferably does not vary by more than about 95-105% from dose to dose.

Buffering Agents

Buffering agents are not critical to the invention, but are preferablyused to provide a rapid rate of onset for the final pharmaceuticalproduct. In a preferred embodiment for powder sachets, the bufferingagent controls the pH of the formulation when dissolved in water, andpreferably yields a pH greater than about 6.8, 7.0, 7.2, or 7.4, andless than about 7.8, 7.7 or 7.6, when mixed with 50 ml or 100 or 200 ml.of water at 25 degrees Celsius.

Particularly preferred buffering agents are alkali metal carbonates andbicarbonates and these agents are preferably employed in a weight ratiorelative to the diclofenac of greater than about 1:5, 2:5, 2:1, 3:1 or5:1. If desired, an upper limit on the buffer:diclofenac ratio can beplaced at about 20:1, 10:1, 5:1, 1:1, 4:5 or 3:5. Ranges can be selectedfrom any two of the foregoing values that are mathematically possible.In a preferred embodiment, the buffer:diclofenac weight ratio rangesfrom about 1:5 to about 4:5. Particularly preferred alkali metalbicarbonates are sodium bicarbonate and potassium bicarbonate.

Final Powdered Sachet Product

The powder sachets used in the methods of this invention can be producedby various methods including dry granulation, wet granulation and dryadmixing processes. A suitable product produced by wet granulation isdescribed, for example, by Reiner et al. in WO 97/44023.

In one clinical trial, a representative 50 mg. diclofenac formulationobtained by the method disclosed in examples 3 and 4 was shown toexhibit the following pharmacokinetic properties:

C_(max) mean value 1620 ng/ml (CV = 53.8%) t_(max) mean value 13.98 min(CV = 32.2%) AUC 0-t mean value 1010 (CV = 42.4%)

In contrast, a 50 mg. formulation prepared by the wet granulationprocess disclosed in WO 97/44023 has been shown to exhibit the followingpharmacokinetic properties:

C_(max) mean value 2213 ng/ml (CV = 33.57%) t_(max) mean value 13.68 min(CV = 16.3%) AUC 0-t mean value 1332.99 (CV = 26.86%)

In one embodiment the powdered sachet is produced by a dry mixingprocess and is characterized by the presence of diclofenac particleshaving one of the particle size distributions described above. Inanother embodiment the product is characterized by the total amount ofpowder used to fill a sachet, which is preferably greater than 500, 600,700 or 800 mg., and/or less than 1800, 1600, 1400, 1200, or 1000 mg.,based on a 50 mg. diclofenac sachet. A preferred amount of powder is 900mg. and the amount preferably does not vary outside the 855-945mg/sachet range per package.

In still another embodiment the invention is characterized by thesolubility of the product in water, the amount of water required tosolubilize the product, and the time required to solubilize the productin a given amount of water. Therefore, in one embodiment a unit dose ofthe sachet is greater than 75% or 85% soluble or is completely solublein 50 ml. of water at 25 degrees Celsius. In another embodiment the unitdose is greater than 75% or 85% solubilized or is completely solubilizedin 50 ml. of water with stirring at 25 degrees Celsius in less than 5minutes. This optimized solubility seems to restrict absorption to ashorter part of the gastrointestinal tract, most likely contributing tothe faster absorption rate and to the lower variability in theabsorption compared to immediate release diclofenac potassium tablets.

The water content of the final product is preferably less than about1.5%. The final product is also preferably free of sugar (saccharose),preferably includes as sweeteners aspartame and/or saccharin, andpreferably includes as flavoring agents anise and/or mint.

Practically any container that maintains hermetic conditions could beused for packaging the powder sachets, though preferably the containerconsists of a sachet that is hermetically sealed in four directions tomaintain the product in hermetic conditions during storage. The sachetis preferably made from a three-layer coupledpaper/aluminum/polyethylene foil in which the weight of the paper isfrom about 0.475 to about 0.525 g/100 cm², the weight of the aluminum isfrom about 0.203 to about 0.229 g/100 cm², and the weight of thepolyethylene is from about 0.295 to about 0.365 g/100 cm².

Diluents for Powder Sachets

Diluents or “filler excipients” are preferably added to increase theresulting dosage units' bulk, and to improve blending characteristics.Freely soluble diluents are particularly preferred because they improvethe solubility of the final product. The diluent preferably has asolubility in water at 25 degrees Celsius of greater than about 10, 15or 20 g/100 ml. of water. A particularly preferred diluent is mannitol,which is substantially non-hygroscopic, and which has a solubility inwater of 22 g/100 ml. Other suitable diluents include lactose, glucose,sucrose, xylitol, and especially lactitol monohydrate due to itsbeneficial non-hygroscopic properties.

The size of the diluent, and the order of adding the diluent during themixing process, have also proven important in the practice of thepresent invention. In a preferred dry mixing process, the diclofenac ismixed with a fine diluent powder before any further processing todistribute the diclofenac and to preserve its flowability. In apreferred wet granulation method, the diclofenac is granulated alongwith coarse diluent powder before any further processing.

The particles sizes for two exemplary fine diluent powders are reportedbelow:

Powder 1 (preferred) Powder 2 Size Distribution (measured by laser) >250μm: not more than 5% >500 μm: not more than 10% >100 μm: not more than25% >315 μm: not more than 25% >20 μm: not less than 55% >40 μm: notless than 60% Size Distribution (measured with sieves) >150 μm not morethan 2% >250 μm not more than 10% Average Particle Size (measure bylaser) 50 micrometers 160 micrometers

The fine diluent powder can also be characterized by its averageparticle diameter, which can range from less than about 200, 180, 160,140, 120, 100, or 80 micrometers, to greater than about 1, 5, 10, 20, 30or 40 micrometers, with ranges defined between any two of the foregoingvalues. Most preferably, the fine diluent powder has an average particlesize of about 50±40, 30, 20 or 10 micrometers.

As a still further alternative, the fine diluent can be characterized byits particle size relative to the diclofenac powder. In such anembodiment, the fine diluent is characterized by an average particlesize of less that 100%, 80%, 60% or 40% of the average particle size ofthe diclofenac powder, and greater that about 5%, 10% or 20% of theaverage particle size of the diclofenac powder, again with rangesdefined between any two of the foregoing values.

In a 50 mg. diclofenac sachet, the weight ratio of fine diluent todiclofenac in the final powder composition is preferably greater thanabout 1:5, 1:2, 1:1 or 1.2:1, and/or less than about 10:1, 6:1, 4:1, 3:1or 2:1, with ranges defined between any two of the foregoing values. Apreferred range of weight ratios is from about 1:1 to about 2:1. In aparticularly preferred embodiment for a 50 mg. diclofenac sachet, thesachet comprises from about 50 to about 100 mg. of the fine diluentparticles, from about 60 to about 85 mg. of fine diluent particles, orfrom about 70 to about 75 mg. of fine diluent particles.

Once the initial mixture of diclofenac and fine diluent powder isprepared in the preferred dry mixing process, a coarser diluent ispreferably used to mix in the remaining components, preferably using astep-addition process in which successive amounts of the coarser diluentare added between each newly added ingredient. A preferred sequence ofmixing, for the dry blending and wet granulation processes, is set forthin the examples hereto. As with the fine diluent, the coarser diluent isalso preferably non-hygroscopic. In a preferred embodiment, the coarserdiluent is the same chemical entity as the fine diluent powder, which ispreferably mannitol. In one embodiment the coarse diluent ischaracterized by an average particle size that is greater than theaverage particle size of the fine diluent, and preferably has an averageparticle size greater than about 120%, 150% or 200% of the averageparticle size of the fine diluent, and less than about 1000%, 800% or600% of the average particle size of the fine diluent, with rangesdefined between any two of the foregoing values.

In an alternative embodiment the coarse diluent is defined by itsparticle size relative to the particle size of the diclofenac powder. Inthis embodiment, the coarse diluent preferably has an average particlesize from about 60, 80 or 100% to about 1000, 800, 600, 400 or 200% ofthe average particle size of the diclofenac powder, with ranges definedbetween any two of the foregoing variables.

In a still further alternative, the coarse diluent can be characterizedas having an average particle diameter of greater than about 75, 85, or100 micrometers, and less than about 300, 250, 200, or 150 micrometers.In a particularly preferred embodiment, the coarse diluent powder hasthe following size distribution:

-   -   >315 μm: not more than 10%    -   >75 μm: not less than 90%

The amount of the coarse diluent is not critical, though it is typicallyadded in an amount to bring the total sachet weight up to about 900 mg.in a 50 mg. diclofenac formulation. The total dosage form preferablycomprises from about 200 to about 1500 mg., from about 400 to about 1000mg., from about 500 to about 800 mg., or from about 600 to about 750 mg.of coarse diluent in a 50 mg. diclofenac sachet. In various embodiments,the weight ratio of coarse diluent to diclofenac in a 50 mg. diclofenacsachet is greater than about 2:1, 4:1, 6:1, 8:1 or 10:1, and less thanabout 40:1, 30:1, 20:1 or 15:1. A preferred range of weight ratios ofthe coarse diluent powder to the diclofenac in a 50 mg. diclofenacsachet is from about 10:1 to about 20:1.

The invention can also be defined by the total amount of non-hygroscopicdiluent (fine and coarse) relative to the amount of diclofenac and, invarious embodiments for a 50 mg. diclofenac sachet, the weight ratio isgreater about 1.5:1, 2:1, 4:1, 6:1, 8:1, 10:1, or 12:1, and less thanabout 80:1, 60:1, 40:1, 30:1, 25:1 or 20:1. In other embodiments, thetotal weight of the non-hygroscopic diluent is greater than about 40%,50%, 60% or 70%, and less than about 95%, 90% or 85% of the weight ofthe total composition in the sachet.

Alternative Doses and Diluent/Diclofenac Ratios

As discussed above, the foregoing weight ratios and relative quantitiesof diclofenac to fine diluent, coarse diluent and total diluent aregiven for a 50 mg. diclofenac sachet, preferably in a 900 mg.formulation. It will be understood that the total volume of the sachetcan be divided or increased by various factors, such as 1.5, 2 or 4while maintaining the foregoing weight ratios, to lower or increase thetotal amount of the diclofenac in the formulation. Thus, for example, a900 mg. sachet containing 50 mg. of diclofenac potassium, 648 mg. ofcoarse diluent and 73 mg. of fine diluent, could be divided in two toprovide a 450 mg. sachet containing 25 mg. of diclofenac potassium, 324mg. of coarse diluent, and 36.5 mg. of fine diluent, or it could bedivided in four to provide a 225 mg. sachet containing 12.5 mg. ofdiclofenac, 162 mg. of coarse diluent and 18.25 mg. of fine diluent.

It is also possible to simply divide the 50 mg. of diclofenac in thesachets described above in half, and provide 25 mg. diclofenac sachetswhile keeping the amounts of fine and coarse diluent substantiallyconstant by, for example, basically doubling the ratios of fine diluentand coarse diluent to diclofenac reported above. Thus, for example, onecould prepare 25 mg. of diclofenac in a 900 mg. sachet usingsubstantially the same amounts of fine and coarse diluent as reportedabove, simply by dividing the total diclofenac in the formulation bytwo. Once again, the total volume of such a sachet could be divided orincreased by various factors, such as 1.5, 2 or 4 while maintaining therevised weight ratios, to lower or increase the total amount of thediclofenac in the formulation.

Lubricants for Powder Sachets

While the use of lubricants is not strictly necessary, in a preferredembodiment they are added to the powder to prevent the powder fromsticking to the metering machine in the final stage of filling thesachets. Suitable lubricants include magnesium stearate, stearic acid,hydrogenated castor oil, talc, or mixtures thereof, but a preferredlubricant is glycerol dibehenate. The lubricant is preferably present inan amount of from about 0.01 to about 2 wt. %, and preferably about 0.2%w/w, based on the weight of the powder composition.

In the method of manufacturing the product, the lubricant is preferablymixed with the diclofenac/fine diluent mixture as a separately preparedpremix that also comprises diluent, albeit in a coarser particle size.

Powder Sachet Processing

In a preferred embodiment the powder sachets used in the invention aremade by a dry blending process in which the diclofenac powder and otheringredients are added sequentially to successive batches of diluent. Ina particularly preferred embodiment, the diclofenac is first blendedwith the fine diluent followed by the successive addition of coarseparticulate and further inactive ingredients.

Therefore, in one embodiment the diclofenac composition is a particulateflowable diclofenac composition made by a process comprising: (a) mixingpowdered diclofenac with a fine powdered diluent to form a firstmixture; and (b) mixing said first mixture with a coarse powdereddiluent to form a second mixture. The second mixture is preferablyobtained by adding the first mixture to a predefined volume of thecoarse diluent, which has preferably been pre-loaded into a mixingmachine. In a further embodiment the method of making the compositionadditionally comprises:

-   -   a) mixing said second mixture with an alkali metal bicarbonate        to form a third dry mixture;    -   b) mixing said third mixture with coarse diluent to form a        fourth mixture;    -   c) mixing coarse diluent with a lubricant to form a fifth        mixture; and    -   d) mixing said fourth and fifth mixtures.

While the preferred method of manufacturing the compositions of thepresent invention is dry blending, other methods can also be employedthat do not depend on mixing of dry powders including wet granulation.For wet granulation, the binder can be added dry to the powder blend, oras a solution in the solvent. The solvent is usually ethanol, water, ora mixture of both. The actual granulation is performed in either ahigh-shear, or low-shear type mixer. Low-shear granulation requirescheaper equipment and produces a more porous granule. High-sheargranulation is faster and affords good control over particle size.

Fluid bed wet granulation is a variation of the process in which thegranulation and drying is carried out in the same vessel (a fluid bedgranulator). The powder mix is fluidized by dry air inside a chamber.The binder solution is sprayed onto the fluidized powder to form theagglomerates. Air fluidizing continues until the agglomerates are dry.The process requires expensive equipment, but is simpler and produces avery porous low-density granule, which can result in faster drugdissolution. Slow drug dissolution is sometimes a problem associatedwith wet granulation, as the active ingredient is locked into thegranule, and initial tablet disintegration liberates the granules ratherthan the primary drug particles.

In dry granulation, particle size enlargement is achieved by aggregatingthe powder particles under high pressure (i.e., by compaction) thenmilling the compressed material to the desired size. Fines generated bymilling are recycled back through the compactor. The compression step istypically carried out in a roller compactor in which the powder iscompressed between two rollers.

Therefore, in another embodiment the invention provides a method ofmaking a wet granulated powder formulation of diclofenac comprising: (a)wet granulating an admixture of diclofenac (or a pharmaceuticallyacceptable salt thereof), a first portion of coarse mannitol, and asuitable bicarbonate to form a wet granulate; and (b) admixing said wetgranulate with a second portion of coarse mannitol and fine mannitol. Inanother embodiment the invention provides a method of making a wetgranulated powder formulation of diclofenac comprising: (a) wetgranulating an admixture of diclofenac (or a pharmaceutically acceptablesalt thereof), a first portion of mannitol and optionally a bicarbonateto form a wet granulate; and (b) admixing said wet granulate with asecond portion of mannitol, wherein the weight ratio of mannitol anddiclofenac in said final formulation is greater than about 1.5:1.

Further subembodiments of the foregoing principal embodiments can bedefined by one or more of the following additional parameters:

-   -   the wet granulation is performed in ethanol;    -   the method further comprises admixing said wet granulate with        glyceryl dibehenate.    -   the wet granulate comprises from about 8 to about 15 weight        parts diclofenac (preferably 10 to 13 weight parts), from about        12 to about 20 weight parts coarse mannitol (preferably 15 to 18        weight parts); and from about 3 to about 7 weight parts        bicarbonate (preferably 4 to 6 weight parts).    -   wet granulate including from about 8 to about 15 weight parts        diclofenac (preferably 10 to 13 weight parts) is admixed with:        from about 100 to about 160 weight parts coarse mannitol        (preferably 120 to 140 weight parts); from about 12 to about 20        weight parts fine mannitol (preferably 14 to 18 weight parts);        and from about 0.2 to about 0.7 weight parts glyceryl dibehenate        (preferably 0.4 to 0.5 weight parts), preferably in sequential        order while stirring.    -   the formulation comprises: fine mannitol and diclofenac or a        pharmaceutically acceptable salt thereof at a weight ratio of        from about 1:2 to about 5:1, coarse mannitol and diclofenac or a        pharmaceutically acceptable salt thereof at a weight ratio of        from about 2:1 to about 40:1, wherein: said fine diluent has an        average particle size of from about 10 to about 180 micrometers,        said coarse diluent has an average particle size of from about        85 to about 250 micrometers, and said coarse diluent has an        average particle size greater than the average particle size of        said fine diluent.    -   said mannitol comprises fine mannitol and coarse mannitol at a        weight ratio of from about 1:5 to about 1:20; said fine mannitol        has the following particle size distribution: 250 μm: not more        than 5%; 100 μm: not more than 25%; 20 μm: not less than 55%;        and said coarse diluent has the following particle size        distribution: 315 μm: not more than 10%; and >75 μm: not less        than 90%.    -   A weight ratio of mannitol to diclofenac of greater about 1.5:1,        2:1, 4:1, 6:1, 8:1, 10:1, or 12:1, and less than about 80:1,        60:1, 40:1, 30:1, 25:1 or 20:1.    -   Total mannitol percentage greater than about 40%, 50%, 60% or        70%, and less than about 95%, 90% or 85%, of the weight of the        total composition in the sachet.        Liquid Formulations

The invention further provides methods for using diclofenac compositionsthat are provided as liquids having the diclofenac already dissolvedtherein. Practically any sort of single use “vial” can be used forcontaining a liquid dosage form. For purposes of this application,“vial” means a small glass container sealed with a suitable stopper andseal, or any other suitable container such as breakable andnon-breakable glass and plastic vials, miniature screw-top jars, and anyother type of container of a size capable of holding a small amount ofdiclofenac liquid. Thus, for example, when the diclofenac is formulatedin liquid solutions that contain approximately 50 mg. diclofenacpotassium in every ml. of liquid, the formulation can be packaged in adropper bottle that contains any suitable quantity of liquid, typicallyfrom about 15 to about 100 ml. of solution. The concentration ofdiclofenac in these formulations typically will be about 50 mg/ml, butcould range from about 10 to about 100 mg/ml, including 10, 25, 50, 75and 100 mg./ml. Alternatively, the vial can be a single use vial, whichwould contain a suitable quantity of liquid such as about 15 ml. for a50 mg. dose of diclofenac potassium.

As with the other formulations of this invention, buffering agents canbe used in the drop formulations where a rapid rate of onset is desiredfor the final pharmaceutical product. In a preferred embodiment for thedrop formulation, the buffering agent most preferably imparts a pHranging from about 7 to about 10.5, from about 8 to about 10, from about8.5 to about 9.5, and most preferably about 9.

Drop formulations are preferably prepared in a three step processcomprising (a) dissolving diclofenac in ethyl alcohol to form asolution, (b) mixing said solution with glycerol to form a secondsolution, and (c) mixing said second solution with water to form a thirdsolution. In a further embodiment, a fourth solution is made bydissolving any desired buffers in water, which is then mixed with thethird solution to provide a final solution. The final solutionpreferably comprises from about 35 to about 45 wt. % water, from about25 to about 35 wt. % ethyl alcohol, and from about 15 to about 25 wt. %glycerol.

In another embodiment the liquid solution is characterized by itspharmacokinetics, such as C_(max) (i.e. average concentration of activechemical in the bloodstream after oral ingestion), and its t_(max) (i.e.average time to reach said C_(max)). A representative 50 mg. dropdiclofenac formulation obtained by the method disclosed in examples 6and 7 herein exhibits the following pharmacokinetic properties:

C_(max) mean value 1679 ng/ml (CV = 39.85%) T_(max) mean value 15.0 min(CV = 56%) AUC_(0-t) mean value 1383 (CV = 30.59%)Capsule and Tablet Formulations

Exemplary solid oral formulations contemplated by the present inventionare set forth in Example 12. Preferred C_(max) and t_(max) ranges fortablet and capsule dosage forms of the invention are set forth below:

Mean C_(max) (ng/ml) Mean t_(max) (min) 50 mg. 1300-2300; 1400-2200;5-35; 10-30; diclofenac tablet 1500-2100; 1750-2000; 12-25; 15-20 orcapsule 1600-1900 25 mg. 700-1150; 750-950; 5-35; 10-30; diclofenactablet 800-900; 850-1050; 15-30; 15-25 or capsule 900-1000 12.5 mg.350-650; 400-600; 5-35; 10-30; diclofenac tablet 450-550 15-25 orcapsule

Disintegration times for the tablet and capsule dosage forms of thepresent invention, when tested according to USP 28 <701>, are preferablyless than about 20 minutes, 15 minutes, 10 minutes, 5 minutes, or even 4minutes, and greater than about 1, 2 or 3 minutes, most preferably fromabout 3 to about 5 minutes. In one particular embodiment, the dosageform is a tablet, and the tablet has a disintegration time thatincreases as the hardness of the tablet decreases. In anotherembodiment, the tablet has a disintegration time that increases as themoisture absorption by the tablet increases.

Dissolution times for the tablet and capsule dosage forms of the presentinvention, when tested according to USP 28<711>, based on the time ittakes to dissolve 90 or 95 wt. % of the drug substance, are preferablyless than about 20 minutes, 15 minutes, 10 minutes, 5 minutes, or even 3minutes, and greater than about 1 or 2 minutes. In a preferredembodiment the dissolution profile of the dosage forms of the presentinvention is as follows: not less than 85, 90 or 95% after 15 minutes insimulated intestinal fluid (i.e. water) at pH=6.8.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds claimed herein are made and evaluated, and are intended to bepurely exemplary of the invention and are not intended to limit thescope of what the inventors regard as their invention. Efforts have beenmade to ensure accuracy with respect to numbers (e.g., amounts,temperature, etc.) but some errors and deviations should be accountedfor. Unless indicated otherwise, parts are parts by weight, temperatureis in ° C. or is at room temperature, and pressure is at or nearatmospheric.

Example 1 Comparative Study of Diclofenac-K Sachet, Diclofenac-KTablets, and Placebo in Treatment of Migraine

A randomized, double-blind, double-dummy multi-center, single dose,placebo- and active-controlled crossover study, with an eight hourevaluation was undertaken in adult migraine patients. 328 patients wererandomized among treatments and a comparison made among treatments witha 50 mg. diclofenac potassium sachet formulation, the 50 mg. diclofenacpotassium sugar coated tablet marketed commercially as Cataflam®, andplacebo. Results are reported in Table 1.

TABLE 1 Pain on Verbal Scale Diclofenac-K Diclofenac-K Sachet TabletPlacebo % of % of % of Parameter patients patients patients Pain free at2 hours ITT pop 24.7% 18.5% 11.7% PP pop 23.6% 17.8% 12.9% Mod-sev 24.2%17.0% 12.5% baseline pain Headache response 2 46.0% 41.6% 24.1% hoursSustained response 36.8% 30.9% 18.4% Sustained pain free 22.3% 15.1% 9.4%

Example 2 Comparative Study of Diclofenac-K Sachet, Diclofenac-KTablets, and Placebo in Treatment of Acute Dental Pain

A double-blind, randomized, parallel-group trial compared the analgesicefficacy of single 50 mg doses of diclofenac potassium sachets andtablets with placebo in 184 patients with moderate/severe pain afterextraction of impacted third molar(s). The primary efficacy variable wasthe average pain reduction from baseline during the first 2 hours afterintake of study medication, assessed using a visual analog scale (VAS).During the first 2 hours post-dose sachets and tablets demonstratedsignificantly less pain (P<0.05) versus placebo and sachets were moreeffective than tablets (P<0.05). Onset of analgesic effect (VAS) wasmaintained for 8 hours for sachets and tablets (P<0.05). Fewer patientsremedicated versus placebo and the results for pain relief and intensityassessed on a verbal scale confirmed the findings for VAS painintensity. No safety issues were identified. Results are reported inTable 2.

TABLE 2 Average VAS Pain Reduction from Baseline during the First 2Hours (ITT Population) Treatment effect Average VAS pain reduction in mmand contrast N LS mean (SE) 95% CI P value^(a) Diclofenac Sachet 73 36.3(2.4) 31.7-41.0 <.0001 Diclofenac Tablet 71 29.1 (2.4) 24.4-33.9 <.0001Placebo 39 11.7 (3.1)  5.5-17.8   .0002 Diclofenac Sachet - — 24.7 (3.8)17.3-32.1 <.0001 Placebo (1) Diclofenac Sachet - — 7.2 (3.1)  1.0-13.4<.0001 Diclofenac (2) Tablet Diclofenac Tablet - — 17.5 (3.8) 10.0-24.9<.0001 Placebo (1) LS = least squares, SE—standard error of the mean,CI—confidence interval. All statistics for treatment effects andtreatment contrasts are based on the analysis of covariance model:Average pain reduction = treatment + country + baseline VAS painintensity. ^(a)P values are two-sided for treatment effects (differenceto 0), (1) one-sided P value for verum # placebo, (2) one-sided P valuefor diclofenac potassium sachet < diclofenac potassium tablet − 10(non-inferiority test)

Example 3 Representative 900 mg. Powder Sachet Formulation

Table 3 describes the composition of a representative 900 mg. powdersachet formulation containing 50 g. of diclofenac potassium that issuitable for practicing the present invention.

TABLE 3 Name of the Unit Reference component (mg.) Function standardDiclofenac 50.0 Active substance Ph. Eur. potassium¹ Glycerol 2.0Lubricant Ph. Eur. dibehenate Saccharin sodium 5.0 Sweetening agent, Ph.Eur. Flavoring enhancer Anise flavor 15.0 Flavoring agent In-housespecifications Potassium hydrogen 22.0 Buffering agent Ph. Eur.Carbonate Mint flavor 35.0 Flavoring agent In-house specificationsAspartame 50.0 Sweetening agent, Ph. Eur. Flavoring enhancer Mannitol²721.0 Diluent Ph. Eur. + additional specification Total weight 900.0¹Particle size distribution: Not less than 90% ≦ 500 μm Not less than40% and not more than 70% ≦ 200 μm Not less than 35% and not more than65% ≦ 150 μm Not less than 30% ≦ 100 μm ²As Mannitol “coarse quality”(648.0 mg) and Mannitol “fine quality” (73.0 mg).

Example 4 Manufacturing Process for 900 mg. Powder Sachets Containing 50mg. of Diclofenac Potassium

A representative process for manufacturing 900 mg. powder sachetscontaining 50 mg. of diclofenac potassium is set forth below, using theequipment set forth in Table 1. The manufacture is performed undercontrolled temperature and relative humidity according to the followingprocess.

Step 1 Sieve using a vibrating sieving machine (typically 850 μm) 47.45Kg of Mannitol “fine quality” and 33.15 kg of Diclofenac Potassium. Loadin a high shear mixer and mix for approx. 6 minutes. Repeat this steponce. (pre-mixture 1) 2 Sieve using a vibrating sieving machine(typically 850 μm), and load in a convection mixer (in the followingorder) 120.0 kg of mannitol “coarse quality,” the pre-mixture 1, 100.0kg of mannitol “coarse quality,” 28.6 kg of potassium hydrogencarbonate, 100.0 kg of mannitol “coarse quality,” 65.0 kg of aspartame,100.0 kg of mannitol “coarse quality,” 6.5 kg of saccharin sodium and100.0 kg of mannitol “coarse quality.” Mix for approx. 5 minutes(pre-mixture 2). 3 Sieve using an oscillating sieving machine (typically850 μm), and load in (final the convection mixer, in the followingorder, 72.4 kg of mannitol “coarse mixture) quality,” 52.6 kg of theglidant pre-mixture consisting of 2.6 kg of Glyceryl dibehenate and 50.0kg of mannitol “coarse quality,” 45.5 kg of mint flavour, 100.0 kg ofmannitol “coarse quality,” 19.5 kg of anise flavour and 100.0 kg ofmannitol “coarse quality.” Mix for approx. 7 minutes in order to obtainthe final homogenous mixture to fill into sachets. 4 Fill the finalmixture into sachets at the target weight. (filling)

TABLE 4 Manufacturing equipment Unit operation Type of equipment SievingScreening mill, oscillating bar Premixing (pre-mixture 1) High shearmixer Mixing (pre-mixture 2 and Convection mixer, final mixture)planetary blenders Filling into sachet Powder filler, Volumetric fillingstation

Example 5 Wet Granulated Powder Sachet Manufacturing Process

The manufacture of 50 mg. diclofenac potassium sachets having theformulation prescribed in Example 3, via wet granulation, is set forthin Tables 5 and 6.

TABLE 5 Batch formula Name of the components Amount (kg) Diclofenacpotassium 11.25¹   Glycerol dibehenate 0.450 Saccharin sodium 1.125Anise flavour 3.375 Potassium hydrogen carbonate 4.95  Mint flavour7.875 Aspartame 11.25  Mannitol “fine quality” 16.425  Mannitol “coarsequality” 145.845  Ethyl Alcohol  3.88 * Total 202.5   * Eliminatedduring the drying process of the wet granulate.

TABLE 6 Manufacturing process Step 1 Load in a wet granulator 16.2 kg ofmannitol “coarse quality,” 11.25 kg of diclofenac potassium, 4.95 kg ofpotassium bicarbonate, 1.125 kg of saccharin sodium and 11.125 kg ofaspartame; mix for approx. 5 minutes; add 3.88 kg of ethyl alcohol andmix for 5 minutes; load the wet granulate in oven at 50° C. until thehumidity of granulate is below 1%. 2 Sieve using an oscillating sievingmachine (typically 850 μm) the following excipients: mannitol “coarsequality,” mannitol “fine quality,” glyceryl dibehenate, mint flavour andanice flavour; load the granulate obtained in step 1 in a convectionmixer and add, in the following order, 129.475 kg of mannitol “coarsequality,” 16.425 kg of mannitol “fine quality,” 0.45 kg of glyceryldibehenate, 7.875 kg of mint flavour and 3.375 kg of anise flavour; mixfor approx. 30 minutes 3 Fill the final mixture into sachets at thetarget weight.

Example 6 Representative Drop Formulation (50 mg. DiclofenacPotassium/ml. of Solution)

Table 7 describes a representative formulation for a drop formulation ofdiclofenac in which one milliliter solution contains 50 mg. ofdiclofenac potassium. The formulation is administered by adding thedrops to water and orally ingesting the mixture.

TABLE 7 Drop Solution Composition Reference Names of ingredients Unit(g) Function standards Active ingredients Diclofenac potassium 5.0^(a)Anti-inflammatory Eur. Ph. agent Solution excipients Ethyl alcohol 30.0Solubilizing and Eur. Ph. preservative agent Glycerol 20.0 Solubilizingagent Eur. Ph. Potassium hydrogen 2.5 Buffering agent Eur. Ph. carbonateSaccharin sodium 1.5 Sweetening agent Eur. Ph. Caramel E 150a 0.25Colouring agent Int. standard^(b) Purified water 42.9 Diluent agent Eur.Ph. Total weight^(b) 102.15 ^(a)This amount refers to active substancematerial with 100.0% assay. ^(b)Weight of 100.0 ml of solution (relativedensity = 1.0215 g/ml).

The formulation is preferably contained in a brown colored glasscontainer, equipped with dropper and screw-cap closure, holding 20 or100 ml of Diclofenac potassium solution. The glass container (type III)is suitable for liquid preparations that are for parenteral use. Thedropper is made from polyethylene low density (PE-LD) material,according to food and pharmaceutical regulations. The screw cap is madefrom polypropylene, suitable as child proof closure.

Example 7 Manufacturing Process for Drop Formulation

The raw materials necessary for the production of a pilot standard batchof 250 liters of solution (volume required to fill 12,500 or 2,500bottles with a capacity of 20 ml or 100 ml, respectively) are listed inTable 8.

TABLE 8 Manufacturing formula for a pilot standard batch of 250 litersof solution Names of Ingredients Unit (kg) Active ingredients Diclofenacpotassium^(a) 12.500 Solution excipients Ethyl alcohol 96% 75.000Glycerol 50.000 Potassium hydrogen 6.250 carbonate Saccharin sodium3.750 Caramel E 150a 0.625 Purified water 107.250 Total weight^(b)255.375 ^(a)Analytical specifications of Diclofenac potassium are thesame used for the sachets ^(b)Weight of 250 liters of solution (relativedensity 1.0215 g/ml).

12.5 kg of Diclofenac potassium, 6.25 kg of potassium hydrogencarbonate, 75 kg of ethyl alcohol 96%, 50 kg of glycerol, 3.75 kg ofsaccharin sodium, 0.625 kg of Caramel E 150a and two different amounts(76 kg and 31.25 kg) of purified water are first weighed.

A first mixture is then prepared by adding the ethyl alcohol 96% into amixing vessel and then, under stirring, adding the active ingredientdiclofenac potassium. After stirring for 10-15 minutes, the glycerol isadded and the mixture stirred for another 10-15 minutes. While stirring,76 kg of purified water is added to the mixture and stirred until acomplete clear solution is obtained.

A second mixture is prepared by adding 31.25 kg of purified water into aseparate mixing vessel and, under stirring, adding the remainingexcipients (potassium hydrogen carbonate, saccharin sodium and Caramel E150a). The mixture is stirred for 15-30 minutes.

While stirring, the first mixture is added to the second mixture and theresultant mixture stirred until a complete clear brown solution isobtained. Under mixing, water is added to the solution until a weight of255.375 kg (250 liter of solution) is obtained. The solution isparticle-free filtrated.

Example 8 Additional Drop Formulations (25 mg. Diclofenac Potassium/ml)

Tables 9 and 10 describe representative formulations of drops containing25 mg. of diclofenac potassium per ml. of solution.

TABLE 9 Reference Names of ingredients Unit(g) Function standard Activeingredients Diclofenac potassium 2.50 Anti-inflammatory Eur. Ph. agentSolution excipients Ethyl alcohol 96% 30.00 Solubilizing and Eur. Ph.preservative agent Glycerol 20.00 Solubilizing agent Eur. Ph. Potassiumhydrogen 1.25 Buffering agent Eur. Ph. carbonate Saccharin sodium 1.50Sweetening agent Eur. Ph. Acesulfame 3.00 Sweetening agent Eur. Ph.Caramel E 150a 0.25 Colouring agent Int. standard Mint flavour 1.40Flavouring agent Int. standard Anise flavour 0.60 Flavouring agent Int.standard Purified water Qb to Diluent agent Eur. Ph. 100 ml Total volume100.00

TABLE 10 Reference Names of ingredients Unit (g) Function standardActive ingredients Diclofenac potassium 2.50 Anti-inflammatory Eur. Ph.agent Solution excipients Ethyl alcohol 96% 30.00 Solubilizing and Eur.Ph. preservative agent Glycerol 20.00 Solubilizing agent Eur. Ph.Potassium hydrogen 1.25 Buffering agent Eur. Ph. carbonate Saccharinsodium 1.50 Sweetening agent Eur. Ph. Acesulfame 3.00 Sweetening agentEur. Ph. Caramel E 150a 0.25 Colouring agent Int. standard Cola flavour2.00 Flavouring agent Int. standard Purified water qb a Diluent agentEur. Ph. 100 ml Total volume 100.00

Example 9 900 mg. Powder Sachet Formulation Containing 25 mg ofDiclofenac Sodium

The ingredients of the product diclofenac sodium 25 mg powder for oralsolution (sachets, weighing 900.0 mg) are listed in Table 11 below.

TABLE 11 Reference Names of ingredients Unit (mg.) Function standardActive ingredients Diclofenac sodium 25^(a) mg Anti-inflammatory Eur.Ph. agent Excipients Potassium hydrogen 11.0 mg Buffering agent Eur. Ph.carbonate Mannitol^(b) 698.0 mg Diluent agent Eur. Ph. Mannitol^(c)74.00 g Diluent agent Eur. Ph. Acesulfame Potassium 40.0 mg Sweeteningagent Eur. Ph. Glycerol Dibehenate 2.0 mg Lubricant agent Eur. Ph.(compritol 888 ATO) Mint flavour 15.0 mg Flavouring agent ManufacturerAnise flavour 35.0 mg Flavouring agent Manufacturer Total weight 900.0mg ^(a)This amount refers to active substance material with 100.0%assay. The diclofenac sodium has the following particle sizedistribution: not less than 95% of the particles are less than 500micrometers in diameter, not more than 90% are less than 250 micrometersin diameter, not more than 60% are less than 180 micrometers indiameter, and not more than 30% are less than 125 micrometers.^(b)Pearlitol SD 200, conform to Eur. Ph. ^(c)Mannitol 35, conform toEur. Ph..

Example 10 Method of Preparing 900 mg. Powder Sachets Containing 25 mg.of Diclofenac Sodium

A representative process for manufacturing 900 mg. powder sachetscontaining 25 mg. of diclofenac sodium is set forth below, using theequipment set forth in Table 1. The manufacture is performed undercontrolled temperature and relative humidity according to the followingprocess.

Preparation of the Pre-Mixture

Sieve all the ingredients necessary for the production of the powder,then weigh 1.375 kg of diclofenac sodium, 0.605 kg of potassium hydrogencarbonate, 38.390 kg of mannitol (pearlitol SD 200), 4.070 kg ofmannitol 35, 2.200 kg of acesulfame K, 0.825 kg of mint flavour, 1.930kg of anise flavour and 0.11 kg of glyceryl dibehenate. Load in themixer: diclofenac sodium, potassium hydrogen carbonate, mannitol 35,acesulfame K, mint flavour and anise flavour. Mix for 25 minutes.

Preparation of the Mixture

Transfer the premix into mixer; add mannitol SD 200 and glyceryldibehenate, mix for 30 minutes.

Example 11 Diclofenac K Sachet Bioavailability Comparison

Test Formulations: Diclofenac potassium 50 mg powder for oral solution(Example 4)

Reference Formulation: Diclofenac potassium, 50 mg film-coated tablets,Cataflam by Novartis Pharma

TABLE 12 Test Formulation fasting AUC(0-inf) AUC(0-t) Cmax Tmax Kel T½Statistic (ng*hr/mL) (ng*hr/mL) (ng/mL) (hr) (1/hr) (hr) N 32 33 33 3332 32 Geometric 1201.001 1185.573 1505.296 0.264 0.54616 1.269 mean Mean1232.925 1216.609 1586.502 0.277 0.56938 1.322 SD 283.9458 277.7587513.3048 0.1035 0.167653 0.3803 CV % 23.03 22.83 32.35 37.32 29.45 28.76Median 1177.67 1164.38 1528.20 0.25 0.5389 1.29 Minimum 686.48 668.10800.58 0.17 0.3442 0.74 Maximum 1912.34 1896.02 2800.55 0.67 0.9352 2.01

TABLE 13 Cataflam fasting AUC(0-inf) AUC(0-t) Cmax Tmax Kel T½ Statistic(ng*hr/mL) (ng*hr/mL) (ng/mL) (hr) (1/hr) (hr) N 32 33 33 33 32 32Geometric 1064.370 1045.187 1037.124 0.618 0.56098 1.236 mean Mean1097.185 1077.596 1146.649 0.788 0.58669 1.290 SD 275.9971 272.7532450.9879 0.7524 0.182630 0.3808 CV % 25.16 25.31 39.33 95.53 31.13 29.51Median 1078.28 1059.80 1125.91 0.50 0.5843 1.19 Minimum 537.38 524.43197.17 0.25 0.3378 0.63 Maximum 1975.32 1959.12 1972.74 4.00 1.1013 2.05

Example 12 50 mg. Diclofenac K Tablet Comparison

Test Formulations: T1: Diclofenac potassium 50 mg film-coated tablets,alcohol granulation

-   -   T2: Diclofenac potassium 50 mg film-coated tablets, dry        granulation        Reference Formulation: Diclofenac potassium, 50 mg film-coated        tablets, Voltarene® Rapid by Novartis Pharma        Study design: Single dose, 3-way, crossover randomised on 6        healthy volunteers        Blood samples drawn: 0 (pre-dose), 5, 10, 15, 20, 30, 45, 60, 90        min, 2, 3, 4, 5, 6, 8, 10, 12 h        Assay: LC-MS-MS/LOQ 5 ng/ml

TABLE 14 Formulation of Comparison Tablets T1, K salt, 50 mg, T2, Ksalt, 50 mg, Reference, K salt, 50 mg, tablets tablets Voltaren ® Rapidtablets Description Diclofenac potassium Diclofenac potassium Diclofenacpotassium 50 mg film-coated tablets 50 mg film-coated 50 mg film-coatedtablets (by alcoholic granulation) tablets (by direct compression)Active Diclofenac potassium mg 50 Diclofenac potassium mg 50 Diclofenacpotassium mg 50 ingredient Excipients Potassium bicarbonate mg 22Potassium bicarbonate mg 22 Calcium phosphate Mannitol mg 50 Mannitol400 mg 119.9 Saccharose Maize starch mg 25 Sodium laurylsulfate mg 0.1Maize starch Hydroxypropylmethylcellulose mg 0.2 Polyvinylpyrrolidone mg6 Talc Sodium laurylsulfate mg 0.1 Magnesium stearate mg 2 SodiumPolyvinylpyrrolidone mg 1 Film Coating Opadry carboxymethylcelluloseSodium starch glycollate mg 2.5 Clear (HPMC 2910, Colloidal anhydrousMagnesium stearate mg 4.5 polyethyleneglycol 400) mg 4 silicium Siliciumaerosil FK 160 mg 1 Polyvinylpyrrolidone Coating Opadry ClearMicrocrystalline cellulose (HPMC 2910 and Magnesium stearatepolyethyleneglycol 400) mg 4 Polyethylenglycole Titanidioxide (E171)Iron oxide red (E172) Total 160.3 mg 204 mg weight

TABLE 15 Pharmacokinetics of Comparison Tablets PK results Test 1 (K,Test 2 (K, Reference (K, tablets 50 mg) tablets 50 mg) tablets 50 mg)C_(max) Mean 1873.30 1744.8 1307.0 SD 553.80 572.3 558.4 CV % 29.5 32.842.7 Min 1228.9 1057.4 581.8 Max 2516.5 2468.9 1935.5 AUC Mean 1219 12371168 SD 246 276 282 CV % 20.2 22.3 24.1 Min 874 848 913 Max 1615 16681642 t_(max) Mean 0.31 h (18.6 min) 0.28 h (16.8 min) 0.68 h (40.8 min)SD 0.04 0.07 0.65 CV % 12.9 25.0 95.6 Min 0.25 h (15 min) 0.17 h (10.2min) 0.25 h (15 min) Max 0.33 h (19.8 min) 0.33 h (19.8 min) 2.00 h (120min)

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this invention pertains. It willbe apparent to those skilled in the art that various modifications andvariations can be made in the present invention without departing fromthe scope or spirit of the invention. Other embodiments of the inventionwill be apparent to those skilled in the art from consideration of thespecification and practice of the invention disclosed herein. It isintended that the specification and examples be considered as exemplaryonly, with a true scope and spirit of the invention being indicated bythe following claims.

What is claimed is:
 1. A pharmaceutical formulation comprising mannitoland diclofenac or a pharmaceutically acceptable salt thereof in aparticulate form at a weight ratio of greater than about 1.5:1, wherein:a) said mannitol comprises a fine diluent having an average particlesize of between 10 and 180 micrometers, at a weight ratio of finediluent to diclofenac in the range from 1:2 to 5:1; b) said mannitolfurther comprises a coarse diluent having an average particle diameterof between 75 and 300 micrometers, at a weight ratio of coarse diluentto diclofenac in the range from 10:1 to 20:1.
 2. The formulation ofclaim 1, in a unit dose pack, wherein said pack comprises 900 mg. ofsaid formulation, said diclofenac is in the form of diclofenacpotassium, and said formulation comprises 50 or 25 or 12.5 mg. ofdiclofenac potassium.
 3. The formulation of claim 1, wherein: a) saiddiclofenac is in the form of diclofenac potassium, b) said formulationcomprises fine mannitol and diclofenac potassium at a weight ratio offrom about 1:1 to about 2:1, and c) said fine mannitol has an averageparticle size of from about 20 to about 80 micrometers.
 4. Theformulation of claim 1 wherein said diclofenac is in the form ofdiclofenac potassium, comprising: a) about 50, 25 or 12.5 mg. ofdiclofenac potassium per 900 mg. of said formulation; b) from about 50to about 100 mg. of fine mannitol per 900 mg. of said formulation; andc) from about 600 to about 700 mg. of coarse mannitol per 900 mg. ofsaid formulation.
 5. The formulation of claim 1 wherein said formulationcomprises from about 50 to about 90 wt. % of said mannitol.
 6. Theformulation of claim 1 wherein said formulation is sugar-free.
 7. Theformulation of claim 1 wherein said formulation further comprisesglyceryl dibehenate.
 8. The formulation of claim 1 wherein saidformulation further comprises an alkali metal bicarbonate at a weightratio to said diclofenac of greater than about 1:5.
 9. The formulationof claim 1 wherein said formulation further comprises an alkali metalbicarbonate at a weight ratio to said diclofenac of from about 1:5 toabout 5:1.
 10. The formulation of claim 1 wherein said formulationcomprises less than 1.5% water.
 11. The formulation of claim 1 whereinsaid diclofenac is present in a granulate.
 12. The formulation of claim1 wherein said formulation has an average pH of 7.5 when dissolved in 50ml. of water.
 13. The formulation of claim 1 wherein at least 75% ofsaid formulation dissolves completely in 50 ml. of water at 25 degreesCelsius under continuous stirring for five minutes.
 14. A method ofmaking a wet granulated powder formulation of diclofenac or apharmaceutically acceptable salt thereof comprising: d) wet granulatingin ethanol an admixture of diclofenac or a pharmaceutically acceptablesalt thereof, a first portion of coarse mannitol, and a bicarbonate toform a wet granulate; and e) admixing said wet granulate with a secondportion of coarse mannitol and fine mannitol.
 15. The method of claim14, further comprising admixing said wet granulate with glyceryldibehenate.
 16. The method of claim 14 wherein said wet granulatefurther comprises: a) from about 8 to about 15 weight parts diclofenacpotassium; b) from about 12 to about 20 weight parts coarse mannitol;and c) from about 3 to about 7 weight parts potassium bicarbonate. 17.The method of claim 14 wherein from about 30 to about 60 weight parts ofwet granulate are admixed with: a) from about 100 to about 160 weightparts coarse mannitol; b) from about 12 to about 20 weight parts finemannitol; and from about 0.2 to about 0.7 weight parts glyceryldibehenate.
 18. A powder sachet dosage form formulation wherein: a) saidformulation comprises: i) 50 or 25 mg of diclofenac potassium per 900 mgof said formulation; ii) from 50 to 100 mg. of fine mannitol per 900 mg.of said formulation; and iii) from 600 to 700 mg. of coarse mannitol per900 mg. of said formulation, wherein: b) said fine mannitol has anaverage particle size of between 10 and 180 micrometers, at a weightratio of fine mannitol to diclofenac potassium in the range from 1:2 to5:1; c) said coarse mannitol has an average particle diameter of between75 and 300 micrometers, at a weight ratio of coarse mannitol todiclofenac in the range from 10:1 to 20:1.